Inflammation represents a cascade of physiological and immunological reactions that nature has designed as the first cellular response to noxious stimuli in an effort to localize toxic materials or prevent tissue injury. Clinically, inflammation is a primary disease under acute conditions or is a manifestation of underlying pathophysiological abnormalities in chronic disease, characterized by classic signs of redness, pain, swelling and loss of function.
The inflammatory mediators IFN-gamma, IL-2, IL-4, IL-5, IL-8, and TNF-alpha have been implicated in the initiation and propagation of several inflammatory disorders. For example, IFN-gamma, which acts as a regulator of other pro-inflammatory cytokines, is the nexus of inflammation in autoimmune disorders such as multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), and rheumatoid arthritis (RA). Other IFN-gamma diseases include, vascular dementia, Alzheimer""s disease, cellular and tissue damage seen in graft-versus-host disease, lupus, and the like. Furthermore, it has long been suspected that TNF-alpha serves as the primary cytokine orchestrating the inflammatory cascade of various debilitating diseases such as rheumatoid arthritis (RA), psoriasis, vasculitis, ischemic-reperfusion injury, and inflammatory bowel disease (IBD). In fact, anti-TNF antibodies and receptor decoys, i.e., Remicade and Enbrel have demonstrated efficacy in treating RA and IBD. Other TNF-alpha related diseases include, photo-aging, leprosy, Leishmania, cachexia, endotoxemia, etc. Other disorders mediated by IFN-gamma and/or TNF-alpha include inflammatory bowel diseases (ulcerative colitis and Crohn""s disease), atopic dermatitis, irritant contact dermatitis, osteoarthritis, asthma, chronic pelvic pain, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, conjunctivitis, gastritis, chronic fatigue syndrome, scleroderma, osteoporosis, and numerous other hyperproliferative, inflammatory and degenerative disorders.
Hyperproliferative and inflammatory mucocutaneous disorders affect millions of individuals in the United States every year. Such disorders range from mild to life threatening, and include, for example, skin cancer, atopic dermatitis, psoriasis, and asthma and inflammatory bowel disease due to inflammation of the intestine wall. In addition, extrinsic skin aging can be caused by chronic inflammation and insufficient repair due to repetitive exposures to environmental insults, e.g., ultraviolet radiation. Aging of skin and in particular extrinsic aging can lead to any of a number of skin conditions requiring treatment.
Eczema, also called eczematous dermatitis, is one example of a common inflammatory mucocutaneous disorder. Eczema is a red, itchy, non-contagious inflammation of the skin that may be acute or chronic, with red skin patches, pimples, crusts, or scabs occurring either alone or in combination. The skin may be dry, or it may discharge a watery fluid, resulting in an itching or burning sensation. The affected skin may become infected. The various causes of eczematous dermatitis are classified as either external (irritations, allergic reactions, exposure to certain microorganisms, or chemicals), congenital (inherited predisposition), and environmental (stress, heat, and the like). Eczema may clear for years, only to reappear later at a different site.
Eczema can come in any of several forms, including, most commonly, atopic dermatitis. Atopic dermatitis is very common in all parts of the world. This chronically relapsing inflammatory skin disorder affects about ten percent of infants and three percent of the U.S. population overall. The disease can occur at any age, but is most common in infants to young adults (see, Hanifin J M et al., Arch. Dermatol., 135(12):1551, 2000). The face is often affected first, then the hands and feet. Sometimes dry red patches appear all over the body. In older children the skin folds are most often affected, especially the elbow creases and behind the knees. In adults the face and hands are more likely to be involved. The condition usually improves in childhood or sometime before the age of 25. Most people with atopic dermatitis have family members with similar problems. Severity of the disease can be evaluated by EASI (Eczema Area Severity Index) score (see, Hanifin J M, Exp. Dermatol., 10(1)11-18, 2001).
Another atopic disease, but which affects the lungs rather than the skin, is allergic asthma. Asthma is a chronic lung disease characterized by inflammation of the air passages (see, Busse W W, et al., xe2x80x9cAsthma,xe2x80x9d New Engl. J. Med., 344(5):350-362, 2001). This condition is estimated to affect about 15 million Americans and can be severe and result in death if not treated. A number of factors can exacerbate asthma including, e.g., rapid changes in temperature or humidity, allergies, upper respiratory infections, exercise, stress or smoking (cigarette). Typical treatments include bronchodilators which are given orally or delivered as an aerosol (inhaled), and, for the most difficult cases, corticosteroids. New, effective treatments without steroid-related side effects will be greatly welcome in this disease of increasing prevalence (see, Thomas P S, xe2x80x9cTumor Necrosis Factor-Alpha: The role of this multifunctional cytokine in asthma,xe2x80x9d Immunol. Cell Biol. 79(2):132-140, 2001).
Another example of a mucocutaneous inflammatory disorder is allergic rhinitis (hay fever). Allergic rhinitis is caused by a nasal inflammation in response to an irritant or an allergen. This condition can be seasonal or occur throughout the year (perennial). Typically, allergic rhinitis is treated by the administration of antihistamines either orally or locally (e.g., using nasal sprays). Other examples of mucocutaneous inflammatory disorders include those that involve cornification. Examples of such disorders include lamellar ichthyosis, acne, and rosacea.
Papulosquamous disorders are those characterized, as the name suggests, by scaly papules and plaques. Some of the more common papulosquamous disorders include psoriasis and lichen planus, both of which are manifested by a local inflammation of either the skin or a mucosal tissue (e.g., in the case of oral lichen planus).
Psoriasis is a persistent skin disease that got its name from the Greek word for xe2x80x9citchxe2x80x9d. The skin becomes inflamed, producing red, thickened areas with silvery scales, most often on the scalp, elbows, knees, and lower back. Severe psoriasis may cover large areas of the body. Psoriasis is not contagious, and has some genetic basis, as it is more likely to occur in people whose family members have it. In the United States about 2% of adults have psoriasis (four to five million people). Approximately 150,000 new cases occur each year. The cause of psoriasis is unknown. However, recent discoveries point to an abnormality in the functioning of key white cells in the blood stream triggering inflammation in the skin. Psoriasis is thus thought to be due, at least in part, to an abnormal immune reaction against some component of the skin. This leads to the local expression of cell adhesion molecules, up-regulation of inflammatory cytokines and growth factors, and to infiltration of inflammatory leukocytes into the tissue. As a result, the two hallmark features of psoriasis are local inflammation and epidermal hyperproliferation. The combination of hyperproliferation with incomplete terminal differentiation leads to the formation of a thickened stratum corneum or plaques.
In addition to psoriasis, other hyperproliferative skin disorders include, but are not limited to, basal cell carcinoma, squamous cell carcinoma (Bowen""s disease), keratosis, such as actinic or seborrheic keratosis, and disorders of keratinization, such as ichthyosis and keratoderma. These hyperproliferative skin disorders result from the loss of the regulatory mechanisms that control the proliferation and differentiation of keratinocytes. Basal and squamous cell carcinomas are the most common forms of skin cancer. About 1.3 million cases of skin carcinomas are found in the United States per year. Both basal and squamous cell carcinoma affect the most external layer of the skin, the epidermis, and begin at the basal cell layer and at the upper cell layer of the epidermis, respectively. Although these skin carcinomas are slow growing and usually benign, they can, if not treated, grow and invade other tissues. In the year 2000, skin carcinomas will cause about 1,900 deaths in the United States.
In addition to changes resulting from inflammatory and hyperproliferative disorders, the appearance and characteristics of the skin also change as the body ages. Chronologically aged (intrinsically aged) mucocutaneous surfaces show a slight atrophy of the epidermis with straightening of the rete pegs thus weakening the dermal/epidermal junction measured by a decrease in the threshold for suction bullae. There is a moderate decrease in the number of Langerhans cells. Dryness of the skin is a common phenomenon. In the dermis there is a decrease in cell numbers and a decrease in elastic fibers and thus in skin elasticity. Capillaries are also fragile as evidenced by bruisability. Collagen metabolism is slower, and there is a progressive lowering in concentration of glycosaminoglycans. Sagging of the skin occurs. There is a decreased ability to mount inflammatory responses and an increase in the time of healing after injury.
Aging is accelerated in those areas exposed to environmental insults, such as irritating substances, and sunlight (ultraviolet radiation), due to the development of local skin inflammation. The skin aging process resulting from exposure to sunlight is known as xe2x80x9cphotoaging.xe2x80x9d Photoaging accounts for about 80% of the visible changes of skin aging. It induces deep wrinkles not erased by stretching, pigmentary alterations with areas of hyper- and hypo-pigmentation (actinic lentigines and leukodermas), and a variety of benign, premalignant, and malignant neoplasms. The dermis shows evidence of chronic inflammation with increased cellularity and enlarged fibroblasts. Elastotic degeneration, known as the xe2x80x9cgrenzxe2x80x9d zone, occurs in parts of the upper dermis. This zone is occupied by a basophilic fibrous material separating the dermis from the epidermis and is interpreted as a repair area. Glycosaminoglycan and elastin concentrations are increased.
Skin inflammation and irritation can also be caused by, for example, transdermal drug delivery, irritating drug delivery enhancers or irritating drug substances that are found in pharmaceutical products as well as in skin care products. Examples of irritating drug substances include, but are not limited to, retinoic acid and its derivatives and analogs, alpha-hydroxy acids and anthralin. The discomfort associated with the inflammation and/or irritation may affect the patient""s compliance with the treatment and comfort during drug delivery.
Inflammation of other muco-epithelial membranes could also lead to severely debilitating disorders. The mucosal epithelium of the alimentary tract represents a crucial barrier to a broad spectrum of noxious and immunogenic substances within the intestinal lumen. An impairment of the integrity of the mucosal epithelial barrier is observed in the course of various intestinal disorders including inflammatory bowel diseases (IBD), celiac disease, intestinal infections, and various other diseases. Ulcerative colitis (UC) and Crohn""s disease (CD), collectively termed inflammatory bowel disease (IBD), are chronic spontaneously relapsing enteropathies of unknown etiology. Pharmacotherapy for IBD has essentially been unchanged for over twenty years, with therapy based around 5-aminosalicylic acid (5-ASA) preparations, corticosteroids, antibiotics and immunosuppression (see, Scrip Reports on Gastrointestinal Disorders: New Therapies for the New Millennium, 2000). The most commonly used immuno-suppressive agents include azathioprine, methotrexate, and 6-mercaptopurine. Much of the controversy surrounding optimal use of these drugs in IBD arises as a consequence of methodological deficiencies in many of the early trials combined with the difficulty in consistent patient selection due to the heterogeneous nature of both UC and CD. While these therapies are able to suppress acute disease activity, there are significant side effect profiles. Furthermore, 20-30% of the IBD patients are steroid-resistant. The most recent report on the efficacy of infliximab has generated a great deal of excitement, although the long-term usefulness is unknown. For certain patients, this treatment could be prohibitive since the cost for each treatment approximates $1,000. A cost-effective therapy which can also be used for long-term maintenance treatment will greatly improve morbidity and mortality and thus, overall quality-of-life of the IBD patients.
If the inflammation occurs at the urogenital epithelium, vaginitis, interstitial cystitis, and the like, may develop. Vaginitis is a common gynecologic disorder that is responsible for 10 million office visits to physicians each year. Infectious vaginitis is the most common cause of a vaginal discharge, but other important diagnostic considerations include infectious cervicitis, a physiologic discharge, atrophic vaginitis, and allergic or irritant vaginitis (see, Quan M, Clin. Cornerstone, 3(1):36-47, 2000). Interstitial cystitis (IC) is a disorder of unknown etiology with few effective therapies. Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterized by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8-60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner""s ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). However, none of these therapies were proven effective in treating a large proportion of patients afflicted with IC.
Osteoporosis afflicts 75 million persons in the United States, Europe and Japan and results in more than 1.3 million fractures annually in the United States. Osteoporosis is a disease characterized by decreased bone mass and increased fragility of the remaining bone (see, Dempster et al, J Bone Mineral Res., 1:19-, 1986; Rodan G A et al. 13:S3-S6, 1992). This low bone mass and increased bone fragility leads to a high incidence of fractures experienced by osteoporosis patients. Because osteoporosis is usually asymptomatic until a fracture occurs, family physicians must identify the appropriate timing and methods for screening those at risk. Prevention is the most important step, and women of all ages should be encouraged to take 1,000 to 1,500 mg supplemental calcium daily, participate in regular weight-bearing exercise, avoid medications known to compromise bone density, institute hormone replacement therapy at menopause unless contraindicated and avoid tobacco and excessive alcohol intake. Therapy for osteoporosis is principally centered on the use of agents that block bone resorption and supplementation with vitamin D and calcium. Although these drugs, bisphosphonates, are effective in reducing the risk of subsequent fractures, and modestly increasing bone density, most patients being treated for osteoporosis still have low bone mass and are at greater risk of fracture. Furthermore, due to the poor intestinal absorption of all bisphosphonates, it is crucial to administer these drugs at least 90 minutes before and after meals and to take them with water only (see, Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th Edition, Hardman J G, et al., McGraw-Hill, 1996). With high dose of bisphosphonate use, gastrointestinal discomforts, such as diarrhea, nausea, and the like occur in some patients (Physicians"" Desk Reference, 2001, Medical Economics Company, Inc., Montvale, N.J.). There is definitely an unmet medical need for safe and effective therapy which is suitable for long term treatment for osteoporosis.
Osteoclast activation is a critical cellular process for pathological bone resorption, such as erosions in rheumatoid arthritis (RA) or generalized bone loss. Among many factors triggering excessive osteoclast activity, IL-1, tumor necrosis factor (TNF)-alpha and IFN-gamma play a central role (see, Roux S et al. Arthritis Res 2(6):451-456, 2000; Pratelli L et al. Minerva Med 90(4):101-9, 1999; Evans et al. J Bone Miner Res Mar. 11(3):300-5, 1996). In fact, a study demonstrates that alendronate reduces bone turnover in early rheumatoid arthritis stage and may have a possible antiarthritic effect, or anti-inflammatory effect, in addition to its biological influence on osteoclast activity/function (see, Cantatore F P et al. J Rheumatol 26(11):2318-23, 1996). It follows that compounds which can effectively block IL-1, TNF and IFN-gamma production may provide alternative medical treatment for osteoporosis, especially osteoporosis which is induced by inflammation, such as RA.
In principle, the inflammatory and immune response can be regulated through the use of drugs (see, Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d eds. Hardman et al. Ninth Edition, McGraw-Hill Publishing, 1996). Unfortunately, certain anti-inflammatory drugs presently available produce cytotoxic effects that reflect their initial employment as cancer chemotherapeutics, typically anti-neoplastics. Such drugs effectively kill cells indiscriminately. Corticosteroids are also a mainstay of anti-inflammatory therapy. However, they manifest significant adverse effects, such as inducing Cushingoid features, skin thinning, increased susceptibility to infection, and suppression of the hypothalamic-pituitary-adrenal axis. The use of other immunosuppressive agents such as cyclosporin A can also induce the development of severe side effects, e.g., hypertension and nephrotoxicity. Clearly, new treatments for inflammatory disorders are needed.
Recently, it is becoming increasingly clear that statins, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are the most commonly used agents for treatment of hypercholesteremia, have clinical benefits beyond their ability to lower cholesterol. For example, pravastatin significantly reduces the incidence of organ rejection, transplant vasculopathy, and natural killer (NK) cell cytotoxicity in recipients of heart (Kobashigawa et al. 1995) and kidney transplants (Katznelson et al. 1996). In another heart transplant study, simvastatin was shown to decrease the progression of transplant vasculopathy and to increase patient survival (Wenke et al. 1997), suggesting that the effects of statins in transplant patients may be a drug class effect. In heart and kidney transplant patients, pravastatin treatment significantly inhibits NK cell cytotoxicity beyond that obtained with the baseline regimen, consisting of prednisone, azathioprine, and cyclosporine. It has been suggested that synergism between statins and cyclosporin A could potentially be the basis for the immunosuppression uniquely observed in transplant patients (Katznelson, 1999). In support of this hypothesis, Kurakota et al. (1996) demonstrate that clinically relevant concentrations of simvastatin which are not immunosuppressive themselves, are capable of significantly enhancing the inhibition of human T-cell responses by cyclosporin A in vitro.
Statins have inhibitory effects on lymphocyte proliferation which are dose-dependent and reversed by addition of mevalonate, the immediate product of HMG-CoA reductase, but not cholesterol (Yachnin 1982). As in other cell types, statins cause cell cycle arrest of lymphocytes in G1 (see, Chakrabarti et al., 1991; Vogt et al. 1996; Tatsuno et al. 1997). Reedquist et al. (Reedquist et al. 1995) has also reported that lovastatin inhibits murine B cell proliferation and differentiation, and induces apoptosis following LPS treatment.
As mentioned previously, glucocorticoids, antimetabolites, and cyclosporin-like immunosuppressants, currently the mainstays of treatment for inflammation, are self-limiting due to untoward side effects. Furthermore, treatments are often ineffective and in some cases, no effective treatment exists. In view of the foregoing, it is readily apparent that there is a great need for compounds and methods for effective treatment for a large number of inflammatory disorders. The present invention addresses these and other needs.
The present invention provides compounds, compositions and methods for the treatment of inflammatory disorders. The compounds of the present invention are preferably store-operated calcium influx (SOC) inhibitors which inhibit calcium uptake into non-excitable cells in response to stimulus-mediated depletion of intracellular calcium storage pools. The SOC inhibitors preferably inhibit one or more of the following: calcium-dependent activation of nuclear factor of activated T cells (NFAT), nuclear factor kB (NF-kB), the stress kinases c-Jun N-terminal kinase (JNK) and exocytosis, resulting in the release or elaboration of inflammatory mediators. Advantageously, the compounds of the present invention can be used to treat various inflammatory disorders and can be formulated in various ways as pharmaceutical compositions and used in methods for optimal delivery and efficacy.
As such, the present invention provides methods for treating an inflammatory disease or reducing an inflammatory reaction, comprising administering a SOC inhibitor to inhibit calcium uptake into a cell, thereby treating the inflammatory disease or reducing the inflammatory reaction. Inflammatory diseases to be treated include skin disorders including, but not limited to, atopic dermatitis, psoriasis, neurogenic inflammation, skin photodamage, a cell carcinoma such as basal cell carcinoma, keratosis, and a disorder of keratinization, and inflammatory pulmonary diseases including asthma, allergic rhinitis, chronic obstructive pulmonary disease, and adult respiratory distress syndrome. Other diseases include inflammatory musculoskeletal conditions, inflammatory gastrointestinal conditions, autoimmune diseases, and transplantation treatments. Examples of SOC inhibitors include for example, novel compounds of the present invention and statins in the 6-lactone form such as lovastatin, mevastatin, and simvastatin.
In another embodiment, the present invention provides a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R4 is an optionally substituted alkyl; and
R5 is an optionally substituted alkyl, or alternatively, R4 and R5 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring. In an especially preferred embodiment, R2 is optionally substituted aryl, such as p-fluorophenyl.
In another embodiment, the present invention provides a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R6 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; and
R7 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; or alternatively, R6 and R7 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring. In an especially preferred embodiment, R2 is optionally substituted aryl, such as p-fluorophenyl.
In yet another embodiment, the present invention provides a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R8 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R9 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; or alternatively, R8 and R9 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring. In an especially preferred embodiment, R2 is optionally substituted aryl, such as p-fluorophenyl.
In still yet another embodiment, the present invention provides a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; and
Q is a member selected from the group of hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy. In an especially preferred embodiment, R2 is optionally substituted aryl, such as p-fluorophenyl.
In still yet another embodiment, the present invention provides a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; and
Q is a member selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy. In an especially preferred embodiment, R2 is optionally substituted aryl, such as p-fluorophenyl.
In another embodiment, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising:
a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R4 is an optionally substituted alkyl;
R5 is an optionally substituted alkyl, or alternatively, R4 and R5 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring; and a pharmaceutically acceptable excipient therefor.
In another embodiment, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising: a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R6 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy;
R7 is a member selected from the group consisting of an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; or alternatively, R6 and R7 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring; and a pharmaceutically acceptable excipient therefor.
In yet another embodiment, the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising: a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from of optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy;
R8 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R9 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; or alternatively, R8 and R9 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring; and a pharmaceutically acceptable excipient therefor.
In still another embodiment, the present invention provides a pharmaceutical composition, comprising: a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
Q is a member selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy; and a pharmaceutically acceptable excipient therefor.
In still yet another embodiment, the present invention provides a pharmaceutical composition, comprising: a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is independently a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
Q is a member selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy; and pharmaceutically acceptable excipient therefor.
In still yet another embodiment, the present invention provides a method for blocking calcium influx from the extracellular space, comprising: contacting a cell with a store operated calcium influx (SOC) inhibitor, thereby blocking calcium influx from the extracellular space. The method can be carried out in vivo or in vitro.
In certain aspects, the SOC inhibitor is a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R4 is selected from an optionally substituted alkyl; and
R5 is selected from an optionally substituted alkyl, or alternatively, R4 and R5 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring.
In another embodiment, the SOC inhibitor is a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R6 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; and
R7 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; or alternatively, R6 and R7 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring.
In yet another embodiment, the SOC inhibitor is a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R8 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy;
R9 is a member selected from an optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; or alternatively, R8 and R9 and the carbons to which they are attached, joined to form an optionally substituted aryl or optionally substituted heteroalkyl 5- or 6 membered ring.
In still yet another embodiment, the SOC inhibitor is a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroarylalkoxy; and
Q is a member selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy.
In still yet another embodiment, the SOC inhibitor is a compound having the formula: 
wherein:
R1 is a member selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylene having at least 2 sites of unsaturation, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroaryliminooxyalkyl, optionally substituted heterocyclyl, optionally substituted oximinoaryl and optionally substituted heteroarylalkoxy;
R2 is a member selected from optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkoxy; and Q is a member selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy and hydroxy.
These and other aspects and advantages of the present will become more apparent when read with the figures and detailed description, which follows.
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
As used herein, the term xe2x80x9calkylxe2x80x9d denotes branched or unbranched hydrocarbon chains, preferably having about 1 to about 8 carbons, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, octa-decyl and 2-methylpentyl. These groups can be optionally substituted with one or more functional groups which are attached commonly to such chains, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form alkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a divalent alkyl group as defined above, such as methylene (xe2x80x94CH2xe2x80x94), propylene (xe2x80x94CH2CH2CH2xe2x80x94), chloroethylene (xe2x80x94CHClCH2xe2x80x94), 2-thiobutene xe2x80x94CH2CH(SH)CH2CH2, 1-bromo-3-hydroxyl-4-methylpentene (xe2x80x94CHBrCH2CH(OH)CH(CH3)CH2xe2x80x94), and the like.
The term xe2x80x9calkenylxe2x80x9d denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon double bonds.
The term xe2x80x9calkynylxe2x80x9d refers to branched or unbranched hydrocarbon chains containing one or more carbon-carbon triple bonds.
The term xe2x80x9carylxe2x80x9d denotes a chain of carbon atoms which form at least one aromatic ring having preferably between about 6-14 carbon atoms, such as phenyl, naphthyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, and the like.
The term xe2x80x9cacylxe2x80x9d denotes the xe2x80x94C(O)R group, wherein R is alkyl or aryl as defined above, such as formyl, acetyl, propionyl, or butyryl.
The term xe2x80x9calkoxyxe2x80x9d denotes xe2x80x94ORxe2x80x94, wherein R is alkyl.
The term xe2x80x9camidoxe2x80x9d denotes an amide linkage: xe2x80x94C(O)NRxe2x80x94 (wherein R is hydrogen or alkyl).
The term xe2x80x9caminoxe2x80x9d denotes an amine linkage: xe2x80x94NRxe2x80x94, wherein R is hydrogen or alkyl.
The term xe2x80x9ccarboxylxe2x80x9d denotes xe2x80x94C(O)Oxe2x80x94, and the term xe2x80x9ccarbonylxe2x80x9d denotes xe2x80x94C(O)xe2x80x94.
The term xe2x80x9cheterocyclyl,xe2x80x9d by itself or in combination with another term, means, a cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heterocyclyl group. Examples of heterocyclyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The term xe2x80x9cheteroaryl,xe2x80x9d means an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The rings may each contain from 1 to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The groups can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include aminobenzoheteroazolyl, 2-azanaphthalenyl, bezoxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl 6-quinolyl, thiobenzoxazolyl, thiobenzothiazolyl and thiobenzimidazolyl. Substituents for each of the above noted herteoaryl ring systems listed above. are selected from the group of acceptable substituents described below. The term xe2x80x9cheteroarylalkylxe2x80x9d is meant to include those radicals in which an heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl, phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
The phrase xe2x80x9coptionally substitutedxe2x80x9d means that each of the above radicals (e.g., xe2x80x9calkyl,xe2x80x9d and xe2x80x9carylxe2x80x9d) are meant to include both substituted and unsubstituted forms of the indicated radical.
The terms xe2x80x9ctreatment,xe2x80x9d xe2x80x9ctherapy,xe2x80x9d and the like, include, but are not limited to, changes in the recipient""s status. The changes can be either subjective or objective and can relate to features such as symptoms or signs of the disease or condition being treated. For example, if the patient notes decreased itching, reduced redness, or decreased pain, then successful treatment has occurred. Similarly, if the clinician notes objective changes, such as by histological analysis of a biopsy sample, then treatment has also been successful. Alternatively, the clinician may note a decrease in inflammatory lesions or other abnormalities upon examination of the patient. This would also represent an improvement or a successful treatment. Prevention of deterioration of the recipient""s status is also included by the term. Therapeutic benefit includes any of a number of subjective or objective factors indicating a response of the condition being treated as discussed herein.
xe2x80x9cDrugxe2x80x9d, xe2x80x9cpharmacological agentxe2x80x9d, xe2x80x9cpharmaceutical agentxe2x80x9d, xe2x80x9cactive agentxe2x80x9d, and xe2x80x9cagentxe2x80x9d are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas, also including proteins, peptides, oligonucleotides, and carbohydrates as well as inorganic ions, such as calcium ion, lanthanum ion, potassium ion, magnesium ion, phosphate ion, and chloride ion.
The term xe2x80x9canti-inflammatory agentxe2x80x9d and the like, include, but are not limited to, agents which reduce the extent and/or severity of inflammation and/or other immune responses. Reduction in the extent and/or severity of immune responses includes reduction in redness, swelling, fever, tissue damage, pain, and/or itch. Also included are agents that prevent inflammation from occurring that would otherwise be induced in response to a stimulus, for example, a drug or cosmetic that induces inflammation as a side effect. As used herein, the term can also include anti-allergens, anti-sensitizers, and anti-irritants.
As used herein, the phrase xe2x80x9ca store operated calcium influx inhibitorxe2x80x9d (xe2x80x9cSOCxe2x80x9d) denotes a therapeutic agent which inhibits calcium uptake into a cell. A SOC inhibitor preferably inhibits the activation of nuclear factor of activated T cells (xe2x80x9cNFATxe2x80x9d). Preferably, store-operated calcium influx (SOC) inhibitors inhibit calcium uptake into non-excitable cells in response to stimulus-mediated depletion of intracellular calcium storage pools. The SOC inhibitors preferably inhibit one or more of the following: calcium-dependent activation of nuclear factor of activated T cells (NFAT), nuclear factor kB (NF-kB), the stress kinases c-Jun N-terminal kinase (JNK) and exocytosis, resulting in the release or elaboration of inflammatory mediators. Examples of SOC inhibitors include for example, novel compounds of the present invention and statins in the xcex4-lactone form such as lovastatin, mevastatin, and simvastatin. Statins are known to be HMG-CoA reductase inhibitors acting in an open-chain form. Stains which are SOC inhibitors act at higher concentrations compared to the HMG-CoA reductase inhibition and are present in the xcex4-lactone form. SOC inhibitors are active in the SOC inhibition assay set forth herein.